The hippocampus is a brain region where robust neurogenesis continues throughout adulthood. Hippocampal neurogenesis and hippocampal volume are reduced in humans suffering from depression, and the chronic administration of antidepressants increases neuronal proliferation in this region. Little is known about the specific mechanisms underlying the effects of antidepressants on neuronal proliferation in the hippocampus, and this is an important gap in our knowledge base. Cyclin-dependent kinase inhibitors are proteins that play a major role in restraining cellular proliferation. Our preliminary studies demonstrate that in the mouse, p21, a cyclin-dependent kinase inhibitor, is abundantly expressed in the subgranular zone of the dentate gyrus, the area where hippocampal neurogenesis occurs. In this region, p21 is co-localized with neurons, and its expression is markedly suppressed after chronic treatment with the tricyclic antidepressant imipramine. The decrease in p21 expression is associated with the increase in the number of cells expressing nuclear protein antigen NeuN, a marker for neurons, and with the induction of proliferating cell nuclear antigen PCNA, a marker of cellular proliferation. p21-null mice exhibit increased BrdU incorporation in the subgranular zone, indicating enhanced neuronal proliferation. Our findings strongly suggest that p21 plays a key role in restraining neuronal proliferation in hippocampus, and have led us to hypothesize that the action of antidepressants on neurogenesis occurs via p21 suppression. This exploratory/developmental grant will test this hypothesis and determine whether the common mechanism of different classes of antidepressants is that they increase neuronal proliferation by altering the activity of cell-cycle regulatory proteins. The results of the proposed experiments will generate new and important information on how antidepressants increase neurogenesis, and could lead to the development of novel and potentially more efficacious treatments for depression.